Il existe deux populations d’adipocytes thermogéniques, les adipocytes bruns du tissu adipeux bruns et les adipocytes ‘’brites’’ qui apparaissent au sein du tissu adipeux blanc. Récemment, la caractérisation d’adipocytes bruns et brites fonctionnels chez l’homme adulte a permis d’envisager de nouvelles approches nutritionnelles et thérapeutiques pour traiter l’obésité. Mon projet de thèse a porté sur l’étude des effets des acides gras polyinsaturés ω6 et ω3 d’origine alimentaire sur la conversion des adipocytes blancs en brites, d’abord chez l’homme in vitro puis chez les rongeurs in vivo. Nous avons pu ainsi démontrer que l'acide arachidonique ω6 à l’origine de nombreux métabolites oxygénés, exerce 1) un effet inhibiteur sur la formation des adipocytes brites grâce aux prostaglandines E2 et F2α, et 2) un effet inducteur via la prostacycline. En effet, celle-ci active la conversion des adipocytes blancs en brites par une voie impliquant le récepteur membranaire IP et les récepteurs nucléaires PPARs. En nous basant sur les recommandations nutritionnelles actuelles chez l’Homme, qui ont pris en considération l’insuffisance de l’apport en acides garsω3 par rapport à l’excès des ω6, nous avons pu montrer chez la souris qu’une supplémentation en acides gras ω3 dans le régime alimentaire était capable d’inhiber l’effet néfaste des acides gras ω6 et d’activer le tissu adipeux brun. Nos résultats démontrent l’importance de la biodisponibilité de l’acide arachidonique dans la biologie du tissu adipeux et permettent de renforcer l’idée que le rééquilibrage du ratio ω6/ω3 est un outil de choix dans la prévention du surpoids et de l’obésité et les maladies métaboliques associées / There are two types of thermogenic adipocytes able to use fatty acids and glucose to produce heat. We distinguish brown adipocytes from the brown adipose tissue and ‘’brite’’ adipocytes which occur into the white adipose tissue. Recently, the characterization of functional brown and brite adipocytes in adult humans has led to the consideration of their use to treat obesity by increasing energy expenditure. My thesis project was to study the effect of dietary polyunsaturated fatty acids, on the conversion of white into brite adipocytes, in vitro and in vivo, in humans and rodents respectively. We demonstrated that arachidonic acid ω6, precursor of prostaglandins, has 1) an inhibitory effect on the recruitment of brite adipocytes via prostaglandins E2 and F2α and 2) an activatory effect via prostacyclin. In fact, prostacyclin induces the conversion of white into brite adipocytes through the IP receptor and the PPARs signaling pathways. Based on human present nutritional recommendations, we demonstrated that a supplementation of ω3 fatty acids in mice diet was able to inhibit the negative effect of ω6 fatty acids and activate brown adipose tissue. Our data highlights the importance of arachidonic acid bioavailability on the biology of adipose tissue and reinforce the idea that an equilibrate ω6/ω3 ratio is a tool that can be used to prevent overweight obesity and associated metabolic disorders

Submitted by Jessica Franzão Ganzaroli (jessicaganzaroli@hotmail.com) on 2018-06-14T19:04:24Z No. of bitstreams: 1 Jéssica Franzão Ganzaroli de Oliveira.pdf: 1826504 bytes, checksum: 014ea667caf3e8adf1c194b73c589410 (MD5) / Approved for entry into archive by Fabio Sampaio Rosas null (fabio@dracena.unesp.br) on 2018-06-15T13:16:14Z (GMT) No. of bitstreams: 1 oliveira_jfg_me_dra.pdf: 1826504 bytes, checksum: 014ea667caf3e8adf1c194b73c589410 (MD5) / Made available in DSpace on 2018-06-15T13:16:14Z (GMT). No. of bitstreams: 1 oliveira_jfg_me_dra.pdf: 1826504 bytes, checksum: 014ea667caf3e8adf1c194b73c589410 (MD5) Previous issue date: 2018-04-26 / A relação entre o consumo de ácidos graxos ω-6/ω-3 na dieta é um importante fator para determinar a ingestão adequada de ácidos graxos bem como prevenir o aparecimento de doenças, podendo interferir no desempenho, na qualidade de ovos e no comportamento plasmático dos lipídios das galinhas poedeiras. Estes ovos podem trazer benefícios para os consumidores que estão cada vez mais preocupados com a ingestão de alimentos saudáveis. O objetivo desta pesquisa foi avaliar diferentes relações ômega-6/ômega-3, visando obter incremento no desempenho, nas variáveis bioquímicas séricas e na qualidade dos ovos de galinhas poedeiras às 81 semanas de idade. Para tanto, foram utilizadas 224 poedeiras da linhagem Hysex White com 81 semanas de idade, distribuídas em um delineamento experimental inteiramente casualizado constituído de sete tratamentos com oito repetições de quatro aves por gaiola, perfazendo um total de 56 gaiolas. Os tratamentos experimentais consistiram em sete diferentes relações de ácidos graxos ω-6/ω-3: 1,0:1,0; 2,0:1,0; 4,0:1,0; 8,0:1,0; 16,0:1,0; 32,0:1,0; 64,0:1,0. Para a formulação dessas dietas foram utilizados o óleo de girassol, rico em ômega-6 e o óleo de linhaça, rico em ômega-3. Não foram observadas diferenças significativas para as variáveis de desempenho, exceto para consumo de ração que aumentou linearmente conforme ascendeu a relação ω-6/ω-3 da dieta, destacando que a inclusão de óleo de linhaça em maiores proporções na dieta resultou em menor consumo de ração, indicando que o óleo de linhaça por ser rico em ômega-3 proporciona sensação de saciedade no animal. Os valores encontrados para as variáveis de qualidade de ovos também não apresentaram diferença significativa entre as dietas, sendo possível a suplementação da ração com ácidos graxos polinsaturados, em diferentes relações, sem promover alterações na qualidade de ovos com exceção da unidade Haugh, em que observou-se efeito quadrático, indicando melhor valor para a relação ω-6/ω-3 de 32. Concluiu-se que o aumento na relação ω-6/ω-3 eleva o consumo de ração das galinhas poedeiras. A relação ω-6/ω-3 de 34,64 proporciona maior unidade Haugh de ovos, diminuindo a partir desse ponto. As demais variáveis de desempenho e de qualidade de ovos permanecem inalteradas. As relações ω-6/ω-3 não influenciam as variáveis bioquímicas séricas das galinhas. / The relation between consumption of ω-6/ω-3 fatty acids in the diet is an important factor in determining the adequate intake of fatty acids and preventing the onset of diseases, which may interfere with performance, egg quality and plasma lipids behavior of laying hens. These eggs can bring benefits to consumers who are increasingly concerned about eating healthy foods. The aim of this study was to evaluate different omega-6/omega-3 ratios, and its influence to increase performance, serum biochemical variables and egg quality of laying hens at 81 weeks of age. For this, 224 laying hens of the Hysex White, 81 weeks old, distributed in a completely randomized experimental design consisting of seven treatments with eight replicates of four poultries per cage, making a total of 56 cages. The experimental treatments consisted of seven different fatty acid ratios ω-6/ω-3: 1.0: 1.0; 2.0: 1.0; 4.0: 1.0; 8.0: 1.0; 16.0: 1.0; 32.0: 1.0; 64.0: 1.0. For formulation of these diets we used sunflower oil, rich in omega-6 and linseed oil, rich in omega-3. No significant differences were observed between variables, except about feed intake that increased linearly as ω-6/ω-3 ratio of the diet rose. This result showed that the inclusion of flaxseed oil in higher proportions can lead to lower intake of ration, indicating that flaxseed oil being rich in omega-3 provides animal satiation. Values found for egg quality variables also did not present a significant difference between diets, indicating the possibility to supplement the diet with polyunsaturated fatty acids, in different ratios, without promoting changes in egg quality, except for Haugh unit, in which it observed quadratic effect. By increasing ω-6/ω-3 ratio also increases feed consumption of laying hens, suggesting better value for the ω-6/ω-3 ratio as 32. The ω-6/ω-3 ratio of 34.64 provides higher Haugh unit of eggs, decreasing from that point. Other performance and egg quality variables remain unchanged. The ω-6/ω-3 ratios did not influence the serum biochemical variables of laying hens.

O glioblastoma multiforme (GBM) é a forma mais maligna de tumor cerebral, originado de células astrocíticas e caracterizado pela intensa proliferação, angiogênese e invasão celular pelo parênquima cerebral normal. O ácido gama-linolênico (GLA) mostrou ter ações anti-tumorais, nos processos de proliferação, migração e angiogênese. Utilizou-se o modelo ortotópico de GBM de rato (C6) e o modelo ex vivo tratados com GLA para análise de migração e proliferação celular. Foi observada uma redução da imunomarcação do fator de crescimento para endotélio vascular (VEGF), seu receptor Flt-1 e da metaloproteinase-2 de matriz, com consequente diminuição de vasos após o tratamento com GLA. No modelo ex vivo observou que o GLA reduziu a distância de migração e a mitose das células tumorais e também causou aumento das células tumorais em processo de apoptose. Os resultados revelaram que o GLA foi capaz de modular a expressão de algumas proteínas envolvidas nos processos angiogênico, migratório e proliferativo do GBM, o que sugere a sua utilização no tratamento desta patologia. / Glioblastoma multiforme (GBM) is the most malignant form of brain tumour originating from astrocytes and is characterized by intense proliferation, angiogenesis and cell invasion through the normal brain parenchyma. Gamma-linolenic acid (GLA) has anti-tumour activities in the processes of proliferation, migration and angiogenesis. This study used the orthotopic GBM rat model (C6) and ex vivo model treated with GLA to analyze cell migration and proliferation. Decreased immunostaining was observed for vascular endothelial growth factor (VEGF), its receptor Flt-1 and matrix metalloproteinase-2, with consequent reduction of blood vessels after treatment with GLA. In the ex vivo model GLA reduced the migration distance and mitosis of tumor cells and increased tumour cell apoptosis. The results revealed that GLA was able to modulate the expression of several proteins involved in angiogenesis, migration and proliferation in GBM, supporting the use of GLA in the treatment of this disease.

The cancers of the skin, melanoma and the keratinocyte cancers, basal cell andsquamous cell carcinomas (BCC and SCC), are among the most common cancersin white populations. While ultraviolet radiation (UVR) is their principal cause,links with non-UVR-related factors have also been noted. Ultimately, theinteraction of these elements results in malignancy however, understanding oftheir specific contributions remains incomplete. This thesis reports findings fromsix studies aiming to investigate gaps in current knowledge of the role of UVR andnon-UVR-related risk factors on skin cancer. The papers are groupedaccording to the aspects of skin cancer epidemiology and aetiology they address. The first two papers address the descriptive epidemiology of melanoma inEngland, a country with low ambient solar UVR. They arise from ecologicalstudies using national melanoma registration data and document rising trends inmelanoma incidence by anatomic site (Paper 1), and by region of residence andsocio-economic deprivation (Paper 2). Their findings were consistent with thesuggestion that increases in recreational UVR exposure are driving rises inmelanoma rates. These results emphasise both the need to closely monitor UVRexposure and melanoma trends and the importance of public health campaigns. The second group of three papers considers the assessment of associations ofnutritional factors with keratinocyte cancer. Two studies use data from aprospective cohort to evaluate the relationship between dietary intake (Paper 3)and blood concentrations (Paper 4) of omega-3 and omega-6 polyunsaturatedfatty acids (PUFA) in relation to BCC and SCC risk. Associations with both PUFAtypes were observed. In addition, Paper 5, a three-way correlational assessment,demonstrated that questionnaire and blood circulating levels of omega-3 PUFAwere highly correlated with measures of skin bioavailability. Collectively, thesestudies give evidence for associations of these nutrients with skin cancer and forthe utility of both intake and biomarker measures for assessing the relationships. The final paper explores the relationship between a widely cited non-UVR riskfactor, namely scars and cancers of the skin. It reports a systematic review of allpublished observational studies quantifying this association. While innumerablecase reports were found, quantitative analyses were rare. The review identifieda major gap in the literature where knowledge of scar malignancies is notevidence-based, but rather founded mainly on cumulative anecdotal reporting. Taken together, this body of published work highlights the largely unrecognisedcomplexity of the aetiology of cancers of the skin. Future research must bebroad in scope in order to advance understanding of the interaction betweenUVR and other risk factors and to provide a base for health messages aimed atreducing the burden of these malignancies.

No description available.

No description available.

INTRODUÇÃO: As doenças cardiovasculares (DCV) são a principal causa de morte no mundo, sendo muitos dos fatores de risco passíveis de prevenção e controle. Embora as DCV sejam complexas em sua etiologia e desenvolvimento, a concentração elevada de LDL-c e baixa de HDL-c constituem os fatores de risco modificáveis mais monitorados na prática clínica, embora não sejam capazes de explicar todos os eventos cardiovasculares. Portanto, investigar como intervenções farmacológicas e nutricionais podem modular parâmetros oxidativos, físicos e estruturais das lipoproteínas pode fornecer estimativa adicional ao risco cardiovascular. Dentre os diversos nutrientes e compostos bioativos relacionados às DCV, os lipídeos representam os mais investigados e descritos na literatura. Nesse contexto, os ácidos graxos insaturados (ômega-3, ômega-6 e ômega-9) têm sido foco de inúmeros estudos. OBJETIVOS: Avaliar o efeito da suplementação com ômega-3, ômega-6 e ômega-9 sobre os parâmetros cardiometabólicos em indivíduos adultos com múltiplos fatores de risco e sem evento cardiovascular prévio. MATERIAL E MÉTODOS: Estudo clínico, randomizado, duplo-cego, baseado em intervenção nutricional (3,0 g/dia de ácidos graxos) sob a fórmula de cápsulas contendo: ômega-3 (37 por cento de EPA e 23 por cento de DHA) ou ômega-6 (65 por cento de ácido linoleico) ou ômega-9 (72 por cento de ácido oleico). A amostra foi composta por indivíduos de ambos os sexos, com idade entre 30 e 74 anos, apresentando pelo menos um dos seguintes fatores de risco: Dislipidemia, Diabetes Mellitus, Obesidade e Hipertensão Arterial Sistêmica. Após aprovação do Comitê de Ética, os indivíduos foram distribuídos nos três grupos de intervenção. No momento basal, os indivíduos foram caracterizados quanto aos aspectos demográficos (sexo, idade e etnia) e clínicos (medicamentos, doenças atuais e antecedentes familiares). Nos momentos basal e após 8 semanas de intervenção, amostras de sangue foram coletadas após 12h de jejum. A partir do plasma foram analisados: perfil lipídico (CT, LDL-c, HDL-c, TG), apolipoproteínas AI e B, ácidos graxos não esterificados, atividade da PON1, LDL(-) e auto-anticorpos, ácidos graxos, glicose, insulina, tamanho e distribuição percentual da LDL (7 subfrações e fenótipo A e não-A) e HDL (10 subfrações). O efeito do tempo, da intervenção e associações entre os ácidos graxos e aspectos qualitativos das lipoproteínas foram testados (SPSS versão 20.0, p <0,05). RESULTADOS: Uma primeira análise dos resultados baseada em um corte transversal demonstrou, por meio da análise de tendência linear ajustada pelo nível de risco cardiovascular, que o maior tercil plasmático de DHA se associou positivamente com HDL-c, HDLGRANDE e tamanho de LDL e negativamente com HDLPEQUENA e TG. Observou-se também que o maior tercil plasmático de ácido linoleico se associou positivamente com HDLGRANDE e tamanho de LDL e negativamente com HDLPEQUENA e TG. Esse perfil de associação não foi observado quando foram avaliados os parâmetros dietéticos. Avaliando uma subamostra que incluiu indivíduos tabagistas suplementados com ômega-6 e ômega-3, observou-se que ômega-3 modificou positivamente o perfil lipídico e as subfrações da HDL. Nos modelos de regressão linear ajustados pela idade, sexo e hipertensão, o DHA plasmático apresentou associações negativas com a HDLPEQUENA. Quando se avaliou exclusivamente o efeito do ômega-3 em indivíduos tabagistas e não tabagistas, observou-se que fumantes, do sexo masculino, acima de 60 anos de idade, apresentando baixo percentual plasmático de EPA e DHA (<8 por cento ), com excesso de peso e gordura corporal elevada, apresentam maior probabilidade de ter um perfil de subfrações de HDL mais aterogênicas. Tendo por base os resultados acima, foi comparado o efeito do ômega-3, ômega-6 e ômega-9 sobre os parâmetros cardiometabólicos. O ômega-3 promoveu redução no TG, aumento do percentual de HDLGRANDE e redução de HDLPEQUENA. O papel cardioprotetor do ômega-3 foi reforçado pelo aumento na incorporação de EPA e DHA, no qual indivíduos com EPA e DHA acima de 8 por cento apresentaram maior probabilidade de ter HDLGRANDE e menor de ter HDLPEQUENA. Em adição, observou-se também que o elevado percentual plasmático de ômega-9 se associou com partículas de LDL menos aterogênicas (fenótipo A). CONCLUSÃO: Ácidos graxos plasmáticos, mas não dietéticos, se correlacionam com parâmetros cardiometabólicos. A suplementação com ômega-3, presente no óleo de peixe, promoveu redução no TG e melhoria nos parâmetros qualitativos da HDL (mais HDLGRANDE e menos HDLPEQUENA). Os benefícios do ômega-3 foram particularmente relevantes nos indivíduos tabagistas e naqueles com menor conteúdo basal de EPA e DHA plasmáticos. Observou-se ainda que o ômega-9 plasmático, presente no azeite de oliva, exerceu impacto positivo no tamanho e subfrações da LDL. / INTRODUCTION: Cardiovascular diseases (CVD) are the leading cause of death worldwide and many of the risk factors are likely to prevention and control. While CVD are complex in their etiology and development, a high concentration of LDL-c and low HDL-c are the most investigated modifiable risk factors in clinical practice, although they are not able to explain all cardiovascular events. So investigate how nutritional and pharmacological interventions can modulate oxidative, physical and structural parameters of lipoproteins can provide additional estimate for cardiovascular risk. Among the many nutrients and bioactive compounds related to CVD, lipids represent the most investigated and described in the literature. In this context, the unsaturated fatty acids (omega-3, omega-6 and omega-9) have been focus of numerous studies. OBJECTIVES: To evaluate the effect of supplementation with omega-3, omega-6 and omega-9 on cardiometabolic parameters in adults with multiple risk factors and without previous cardiovascular event. MATERIAL AND METHODS: Clinical trial, randomized, double-blind, based on nutritional intervention (3.0 g/day of fatty acids) containing: omega-3 (37 per cent EPA and 23 per cent DHA) or omega-6 (65 per cent linoleic acid) or omega-9 (72 per cent of oleic acid). Subjects of both sexes, aged between 30 and 74 years old, with at least one of the following risk factors: hyperlipidemia, diabetes mellitus, obesity and hypertension were included. After Ethics Committee approval, the subjects were distributed on the three intervention groups. At baseline the demographic (gender, age and ethnicity) and clinical (medications, current diseases and family history) data were evaluated. At baseline and after 8 weeks of intervention, blood samples were collected after 12 hours of fasting. From the plasma were analyzed: lipid profile (TC, LDLc, HDL-c, TG), apolipoproteins AI and B, non esterified fatty acid, PON1 activity, LDL (-) and autoantibodies, fatty acids, glucose, insulin, size and distribution of LDL (7 subfractions and phenotype) and HDL (10 subfractions). The effect of time, intervention and associations between fatty acids and qualitative aspects of lipoproteins were evaluated (SPSS version 20.0, p <0.05). RESULTS: A first analysis of the results based on a cross sectional study showed through the linear trend analysis, adjusted by the level of cardiovascular risk, that the highest tertile of plasma DHA was positively associated with HDL-c, HDLLARGE and LDL size and inversely with HDLSMALL and TG. The highest tertile of plasma linoleic acid was positively associated with HDLLARGE and LDL size and negatively with HDLSMALL and TG. This association was not observed when we evaluated the dietary parameters. A sample including smokers supplemented with omega-6 and omega-3 showed that omega-3 positively modify the lipid profile and HDL subfractions. In linear regression models adjusted for age, sex and hypertension, plasma DHA showed negative associations with HDLSMALL. When only assessed the effect of omega-3 in smokers and non-smokers, the results showed that smokers, male, over 60 years old, with low percentage of EPA and DHA (<8 per cent ), overweight and/or obese and high body fat have an increased chance to have HDL subfractions profile less cardioprotective. Based on the above results, we compared the effect of omega-3, omega-6 and omega-9 on cardiometabolic parameters. The omega-3 decreased TG, increase the percentage of HDLLARGE and decrease HDLSMALL. The cardioprotective role of the omega-3 was enhanced by increasing the incorporation of EPA and DHA, in which subjects with more than 8 per cent of EPA and DHA were more likely to have HDLLARGE and lower HDLSMALL. In addition, it was also observed that higher omega-9 plasma levels was associated with less atherogenic LDL particles (phenotype A). CONCLUSION: Plasma fatty acids, but not dietary, correlate with cardiometabolic parameters. Supplementation with omega-3, present in fish oil, promoted reduction in TG and improved the qualitative parameters of HDL (more HDLARGE and less HDLSMALL). The benefits of omega-3 were particularly significant in smokers and those with lower baseline content of EPA and DHA. It was also observed that omega-9, present in olive oil, had a positive impact on the size of LDL.

During the 21 day incubation period, the fertile egg provides nutrients such as fatty acids for energy and polyunsaturated fatty acids (PUFA) for membrane synthesis to the developing chick. The hypothesis tested in the present study is that the type of PUFA fed to the breeder hen can alter tissue lipid composition and PUFA metabolism in the progeny during growth. The objective of the present study was to test two different sources of PUFA (n-3 or n-6) on: 1) egg production, egg, and chick quality; and 2) changes in tissue PUFA composition and metabolism in progeny during growth. Fertilized eggs (n=240) were collected from Ross breeder hens (n=45) fed one of the three experimental diets containing 3.5% fish (long chain n-3), flax (18:3 n-3), or safflower oil (18:2 n-6). The egg and yolk weight was lowest for eggs from hens fed fish oil (P=0.09, P=0.02). The chick weight on day of hatch was 41.2, 45.3, and 43.3g, for fish, flax, and safflower, respectively (P=0.003). In the second experiment fertilized eggs were collected from Lohman Brown layer hens (n=75) fed a control, high n-3, or low n-3 diet. Chicks were raised up to day 14 on a control diet lacking long-chain n-6 and n-3 fatty acids. Chick tissue samples (gastrointestinal tract, liver, and blood) were collected on day 1, 7, and 14 and were subjected to fatty acid (FA) and interleukin-6 (IL-6) analysis. The long-chain n-6 to long chain n-3 ratio was lowest in the duodenum, jejunum, ileum, and liver from chicks hatched from fish oil fed hens (P<0.001) up to day 14. Interleukin-6 was lowest in liver (P=0.009) and serum on day of hatch, for fish oil chicks. The results from this study show that the diet fed to breeder hens alters progeny tissue PUFA composition and lipid metabolism during early development in avians. The long term effects of maternal diet manipulation on progeny growth and lipid metabolism need to be investigated in detail. / Graduation date: 2013

A few abnormal cells found in a small piece of prostate tissue are most consequential for a man’s future. The prevalence of prostate cancer (PCa) is increasing globally. The main instigating factor for this cancer is not yet known, but it appears to be the consequence of many variables such as an increasingly older population, more frequent PSA-testing, and factors involving lifestyle. Prostate cancer screening, as an equivalent for breast cancer screening, has been suggested but unfortunately there are no accurate diagnostic tools available for this type of screening. The reason for this is simply that the prostate is one of the most difficult organs to diagnose and, consequently, PCa screening would generate far too many false-positive and false-negative results.  The prostate is not easily accessible as it is deeply-seated in the male pelvic area, wrapped around the urethra and surrounded by sensitive vital organs.  Furthermore, PCa is frequently multi-focal, and the cancer cells have a tendency of assimilating among normal cells and, thus, do not always form solid lumps.  Therefore, prostate tumors are often not felt by digital rectal examination (DRE) or identified by imaging.  The PSA-test is not reliable as it is more prostate-specific than cancer-specific.  Due to increasing prostate awareness, more early-stage and locally confined PCa are being detected. This is saving lives, although there is a high risk of over treatment and unnecessary side-effects.  The increased detection of PCa requires sophisticated diagnostic methods and highly skilled clinicians who can discern between indolent and aggressive cancers.  The current “gold-standard” for PCa diagnosis is biopsy grading by pathologists using the Gleason score system, which is a difficult task.  Therefore, innovative methods to improve the precision of prostate diagnosis, by increased biopsy sensitivity and tumor localization, are of essence. In light of these difficulties, the metabolomic approach using 1D and 2D high-resolution magic angle spinning (HRMAS) NMR spectroscopy combined with histopathology on intact prostatectomy specimens was evaluated in this research project.  The non-destructive nature of HRMAS NMR enables spectroscopic analysis of intact tissue samples with consecutive histological examinations under light microscope. Metabolomics aids in the unraveling and the discovery of organ-specific endogenous metabolites that have the potential to be reliable indicators of organ function and viability, extrinsic and intrinsic perturbations, as well as valuable markers for treatment response. The results may, therefore, be applied clinically to characterize an organ by utilizing biomarkers that have the capacity to distinguish between disease and health. The aim was to characterize the human and the rat prostate in terms of its intermediary metabolism, which I show here to differ between species and anatomical regions.  Furthermore, the aim is to seek the verification of HRMAS NMR derived metabolites which are known to be a part of the prostate metabolome such as, citrate, choline, and the polyamines which were performed, but also the identification of metabolites not previously identified as part of the local prostate metabolism, such as Omega-6, which was detected in tumors.  The extended aim was to elucidate novel bio-markers with clinical potential. In this study, the common phyto-nutrient, inositol, which appears to possess protective properties, was identified as being a potentially important PCa bio-marker for the distinction between the more indolent Gleason score 6 and the more aggressive Gleason score 7 in non-malignant prostate tissues with tumors elsewhere in the organ. Further studies in this area of PCa research are therefore warranted.

INTRODUÇÃO: As doenças cardiovasculares (DCV) são a principal causa de morte no mundo, sendo muitos dos fatores de risco passíveis de prevenção e controle. Embora as DCV sejam complexas em sua etiologia e desenvolvimento, a concentração elevada de LDL-c e baixa de HDL-c constituem os fatores de risco modificáveis mais monitorados na prática clínica, embora não sejam capazes de explicar todos os eventos cardiovasculares. Portanto, investigar como intervenções farmacológicas e nutricionais podem modular parâmetros oxidativos, físicos e estruturais das lipoproteínas pode fornecer estimativa adicional ao risco cardiovascular. Dentre os diversos nutrientes e compostos bioativos relacionados às DCV, os lipídeos representam os mais investigados e descritos na literatura. Nesse contexto, os ácidos graxos insaturados (ômega-3, ômega-6 e ômega-9) têm sido foco de inúmeros estudos. OBJETIVOS: Avaliar o efeito da suplementação com ômega-3, ômega-6 e ômega-9 sobre os parâmetros cardiometabólicos em indivíduos adultos com múltiplos fatores de risco e sem evento cardiovascular prévio. MATERIAL E MÉTODOS: Estudo clínico, randomizado, duplo-cego, baseado em intervenção nutricional (3,0 g/dia de ácidos graxos) sob a fórmula de cápsulas contendo: ômega-3 (37 por cento de EPA e 23 por cento de DHA) ou ômega-6 (65 por cento de ácido linoleico) ou ômega-9 (72 por cento de ácido oleico). A amostra foi composta por indivíduos de ambos os sexos, com idade entre 30 e 74 anos, apresentando pelo menos um dos seguintes fatores de risco: Dislipidemia, Diabetes Mellitus, Obesidade e Hipertensão Arterial Sistêmica. Após aprovação do Comitê de Ética, os indivíduos foram distribuídos nos três grupos de intervenção. No momento basal, os indivíduos foram caracterizados quanto aos aspectos demográficos (sexo, idade e etnia) e clínicos (medicamentos, doenças atuais e antecedentes familiares). Nos momentos basal e após 8 semanas de intervenção, amostras de sangue foram coletadas após 12h de jejum. A partir do plasma foram analisados: perfil lipídico (CT, LDL-c, HDL-c, TG), apolipoproteínas AI e B, ácidos graxos não esterificados, atividade da PON1, LDL(-) e auto-anticorpos, ácidos graxos, glicose, insulina, tamanho e distribuição percentual da LDL (7 subfrações e fenótipo A e não-A) e HDL (10 subfrações). O efeito do tempo, da intervenção e associações entre os ácidos graxos e aspectos qualitativos das lipoproteínas foram testados (SPSS versão 20.0, p <0,05). RESULTADOS: Uma primeira análise dos resultados baseada em um corte transversal demonstrou, por meio da análise de tendência linear ajustada pelo nível de risco cardiovascular, que o maior tercil plasmático de DHA se associou positivamente com HDL-c, HDLGRANDE e tamanho de LDL e negativamente com HDLPEQUENA e TG. Observou-se também que o maior tercil plasmático de ácido linoleico se associou positivamente com HDLGRANDE e tamanho de LDL e negativamente com HDLPEQUENA e TG. Esse perfil de associação não foi observado quando foram avaliados os parâmetros dietéticos. Avaliando uma subamostra que incluiu indivíduos tabagistas suplementados com ômega-6 e ômega-3, observou-se que ômega-3 modificou positivamente o perfil lipídico e as subfrações da HDL. Nos modelos de regressão linear ajustados pela idade, sexo e hipertensão, o DHA plasmático apresentou associações negativas com a HDLPEQUENA. Quando se avaliou exclusivamente o efeito do ômega-3 em indivíduos tabagistas e não tabagistas, observou-se que fumantes, do sexo masculino, acima de 60 anos de idade, apresentando baixo percentual plasmático de EPA e DHA (<8 por cento ), com excesso de peso e gordura corporal elevada, apresentam maior probabilidade de ter um perfil de subfrações de HDL mais aterogênicas. Tendo por base os resultados acima, foi comparado o efeito do ômega-3, ômega-6 e ômega-9 sobre os parâmetros cardiometabólicos. O ômega-3 promoveu redução no TG, aumento do percentual de HDLGRANDE e redução de HDLPEQUENA. O papel cardioprotetor do ômega-3 foi reforçado pelo aumento na incorporação de EPA e DHA, no qual indivíduos com EPA e DHA acima de 8 por cento apresentaram maior probabilidade de ter HDLGRANDE e menor de ter HDLPEQUENA. Em adição, observou-se também que o elevado percentual plasmático de ômega-9 se associou com partículas de LDL menos aterogênicas (fenótipo A). CONCLUSÃO: Ácidos graxos plasmáticos, mas não dietéticos, se correlacionam com parâmetros cardiometabólicos. A suplementação com ômega-3, presente no óleo de peixe, promoveu redução no TG e melhoria nos parâmetros qualitativos da HDL (mais HDLGRANDE e menos HDLPEQUENA). Os benefícios do ômega-3 foram particularmente relevantes nos indivíduos tabagistas e naqueles com menor conteúdo basal de EPA e DHA plasmáticos. Observou-se ainda que o ômega-9 plasmático, presente no azeite de oliva, exerceu impacto positivo no tamanho e subfrações da LDL. / INTRODUCTION: Cardiovascular diseases (CVD) are the leading cause of death worldwide and many of the risk factors are likely to prevention and control. While CVD are complex in their etiology and development, a high concentration of LDL-c and low HDL-c are the most investigated modifiable risk factors in clinical practice, although they are not able to explain all cardiovascular events. So investigate how nutritional and pharmacological interventions can modulate oxidative, physical and structural parameters of lipoproteins can provide additional estimate for cardiovascular risk. Among the many nutrients and bioactive compounds related to CVD, lipids represent the most investigated and described in the literature. In this context, the unsaturated fatty acids (omega-3, omega-6 and omega-9) have been focus of numerous studies. OBJECTIVES: To evaluate the effect of supplementation with omega-3, omega-6 and omega-9 on cardiometabolic parameters in adults with multiple risk factors and without previous cardiovascular event. MATERIAL AND METHODS: Clinical trial, randomized, double-blind, based on nutritional intervention (3.0 g/day of fatty acids) containing: omega-3 (37 per cent EPA and 23 per cent DHA) or omega-6 (65 per cent linoleic acid) or omega-9 (72 per cent of oleic acid). Subjects of both sexes, aged between 30 and 74 years old, with at least one of the following risk factors: hyperlipidemia, diabetes mellitus, obesity and hypertension were included. After Ethics Committee approval, the subjects were distributed on the three intervention groups. At baseline the demographic (gender, age and ethnicity) and clinical (medications, current diseases and family history) data were evaluated. At baseline and after 8 weeks of intervention, blood samples were collected after 12 hours of fasting. From the plasma were analyzed: lipid profile (TC, LDLc, HDL-c, TG), apolipoproteins AI and B, non esterified fatty acid, PON1 activity, LDL (-) and autoantibodies, fatty acids, glucose, insulin, size and distribution of LDL (7 subfractions and phenotype) and HDL (10 subfractions). The effect of time, intervention and associations between fatty acids and qualitative aspects of lipoproteins were evaluated (SPSS version 20.0, p <0.05). RESULTS: A first analysis of the results based on a cross sectional study showed through the linear trend analysis, adjusted by the level of cardiovascular risk, that the highest tertile of plasma DHA was positively associated with HDL-c, HDLLARGE and LDL size and inversely with HDLSMALL and TG. The highest tertile of plasma linoleic acid was positively associated with HDLLARGE and LDL size and negatively with HDLSMALL and TG. This association was not observed when we evaluated the dietary parameters. A sample including smokers supplemented with omega-6 and omega-3 showed that omega-3 positively modify the lipid profile and HDL subfractions. In linear regression models adjusted for age, sex and hypertension, plasma DHA showed negative associations with HDLSMALL. When only assessed the effect of omega-3 in smokers and non-smokers, the results showed that smokers, male, over 60 years old, with low percentage of EPA and DHA (<8 per cent ), overweight and/or obese and high body fat have an increased chance to have HDL subfractions profile less cardioprotective. Based on the above results, we compared the effect of omega-3, omega-6 and omega-9 on cardiometabolic parameters. The omega-3 decreased TG, increase the percentage of HDLLARGE and decrease HDLSMALL. The cardioprotective role of the omega-3 was enhanced by increasing the incorporation of EPA and DHA, in which subjects with more than 8 per cent of EPA and DHA were more likely to have HDLLARGE and lower HDLSMALL. In addition, it was also observed that higher omega-9 plasma levels was associated with less atherogenic LDL particles (phenotype A). CONCLUSION: Plasma fatty acids, but not dietary, correlate with cardiometabolic parameters. Supplementation with omega-3, present in fish oil, promoted reduction in TG and improved the qualitative parameters of HDL (more HDLARGE and less HDLSMALL). The benefits of omega-3 were particularly significant in smokers and those with lower baseline content of EPA and DHA. It was also observed that omega-9, present in olive oil, had a positive impact on the size of LDL.